4-hydroxy-2-nonenal and cyclopentenone

Reactive aldehydes, such as 4-hydroxy-2-nonenal, have been implicated as inducers in generating intracellular reactive oxygen species and activation of stress signaling pathways, that integrate with other signaling pathways to control cellular responses to the extracellular stimuli. Here, I briefly summarize a novel signaling pathway in cellular response, in which aldehyde-stimulated detoxification response is mediated by cyclooxygenase metabolites. These findings argue that lipid mediators could induce a cellular process that represents a cellular defense program against toxic compounds.

Topics: Aldehydes; Animals; Cyclooxygenase 2; Cyclopentanes; Gene Expression; Glutathione Transferase; Humans; Isoenzymes; Lipid Peroxidation; Membrane Proteins; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Signal Transduction

LKB1, a unique serine/threonine kinase tumor suppressor, modulates anabolic and catabolic homeostasis, cell proliferation, and organ polarity. Chemically reactive lipids, e.g. cyclopentenone prostaglandins, formed a covalent adduct with LKB1 in MCF-7 and RKO cells. Site-directed mutagenesis implicated Cys210 in the LKB1 activation loop as the residue modified. Notably, ERK, JNK, and AKT serine/threonine kinases with leucine or methionine, instead of cysteine, in their activation loop did not form a covalent lipid adduct. 4-Hydroxy-2-nonenal, 4-oxo-2-nonenal, and cyclopentenone prostaglandin A and J, which all contain alpha,beta-unsaturated carbonyls, inhibited the AMP-kinase kinase activity of cellular LKB1. In turn, this attenuated signals throughout the LKB1 --> AMP kinase pathway and disrupted its restraint of ribosomal S6 kinases. The electrophilic beta-carbon in these lipids appears to be critical for inhibition because unreactive lipids, e.g. PGB1, PGE2, PGF2alpha, and TxB2, did not inhibit LKB1 activity (p > 0.05). Ectopic expression of cyclooxygenase-2 and endogenous biosynthesis of eicosanoids also inhibited LKB1 activity in MCF-7 cells. Our results suggested a molecular mechanism whereby chronic inflammation or oxidative stress may confer risk for hypertrophic or neoplastic diseases. Moreover, chemical inactivation of LKB1 may interfere with its physiological antagonism of signals from growth factors, insulin, and oncogenes.

Topics: Aldehydes; AMP-Activated Protein Kinase Kinases; Cell Line, Tumor; Cyclooxygenase 2; Cyclopentanes; Energy Metabolism; Humans; Lipids; Mutagenesis, Site-Directed; Phosphotransferases (Phosphate Group Acceptor); Prostaglandins; Protein Biosynthesis; Protein Serine-Threonine Kinases

Electrophilic eicosanoids of the J series, with their distinctive cross-conjugated alpha,beta-unsaturated ketone, inactivate genetically wild type tumor suppressor p53 in a manner analogous to prostaglandins of the A series. Like the prostaglandins of the A series, prostaglandins of the J series have a structural determinant (endocyclic cyclopentenone) that confers the ability to impair the conformation, the phosphorylation, and the transcriptional activity of the p53 tumor suppressor with equivalent potency and efficacy. However, J series prostaglandins have a unique structural determinant (exocyclic alpha,beta-unsaturated ketone) that confers unique efficacy as an apoptotic agonist. In seeking to understand how J series prostaglandins cause apoptosis despite their inactivation of p53, we discovered that they inhibit the ubiquitin isopeptidase activity of the proteasome pathway. In this regard, J series prostaglandins were more efficacious inhibitors than representative members of the A, B, or E series prostaglandins. Disruption of the proteasome pathway with proteasome inhibitors can cause apoptosis independently of p53. Therefore, this finding helps reconcile the p53 transcriptional independence of apoptosis caused by Delta12-prostaglandin J(2). This discovery represents a novel mechanism for proteasome pathway inhibition in intact cells. Furthermore, it identifies isopeptidases as novel targets for the development of antineoplastic agents.

Topics: Aldehydes; Apoptosis; Biopolymers; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Cyclopentanes; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Endopeptidases; Epitopes; Genes, p53; Humans; Immunohistochemistry; Ketones; Models, Biological; Models, Chemical; Multienzyme Complexes; Peptide Hydrolases; Phosphorylation; Polyubiquitin; Prostaglandins; Proteasome Endopeptidase Complex; Protein Binding; Protein Conformation; Time Factors; Transcription, Genetic; Transcriptional Activation; Transfection; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Ubiquitins